Dr. Dusko Ilic, M.D., Ph.D., has been a postdoctoral fellow for the past three years in Dr. Caroline Damsky's laboratory at UCSF. Dr. Ili knocked out the focal adhesion kinase (FAK) gene in mice while a graduate student at the University of Tokyo. Major insights from the phenotype were that FAK is likely involved in focal adhesion site turnover, rather than formation, and that FAK deficiency in mice results in a phenotype remarkably similar to that of fibronectin (FN) deficiency. In the Damsky lab Dr. Ilic has continued to study the role of FAK in transducing signals from the extracellular matrix (ECM) component FN in fibroblasts and endothelial cells with emphasis on the mechanism of anchorage-dependence for cell survival. Based on the similarity in the FAK- and FN-null phenotypes, the underlying hypothesis of this KO1 fellowship, is that there is a FN-FAK signaling axis, critical for the regulation of fundamental processes relevant to cancer, including survival, cell proliferation and migration. FAK- and FN-null embryos and cells, and their wild-type counterparts, will be used to address this hypothesis. Experiments in Aim 1 will assess the synthesis, organization and function of FN in cells derived from FAK-null embryos, and the localization and signaling functions of FAK in cells derived from FN-null embryos. Experiments in Aim 2 will assess the mechanisms by which signals from FN and individual growth factors cooperate in regulating cell cycle progression and how this is altered in cells that lack FN or FAK. These studies will extend Dr. Ilic's training in the development of in vitro assays for cell behaviors relevant to the cancer phenotype and the in-depth analysis of FAK- and FN-null phenotypes in embryos. Such training will complement his already strong background in molecular biology, preparing him well for an independent research career in academia or biotechnology. The Damsky laboratory and UCSF provide an outstanding environment for these studies. Dr. Damsky has a long track record in studying cell-ECM interactions and integrin function. A hallmark has been in creating in vitro assays that measure adhesive and invasive behaviors, as well as proliferation, survival and gene expression. Studies have been conducted in fibroblasts, melanoma cells, trophoblasts and early mouse embryos. In addition to research, lab meeting, journal clubs and outside seminar speakers provide opportunities to report on research progress and to broaden knowledge. Training opportunities also exist in association with the UCSF Library to keep abreast of new technologies in informatics and information management, and in association with the UCSF Cancer Center to learn microarray technology.